Inhibition of plasma membrane Na+, K+-ATPase activity is well documented to promote neuronal degeneration by enhancing the sensitivity of neurons to glutamate induced excitotoxicity. Dr. Foley has found that, under certain defined conditions, low (millimolar) concentrations of ethanol inhibited synptosomal membrane Na+, K+-ATPase activity by a pathway that was secondary to activation of cyclooxygenase (COX) activity. In addition, he has demonstrated that the COX hydroperoxide product, PGG2, potently inhibited Na+, K+-ATPase activity by an apparent hydroperoxide-dependent mechanism that did not involve formation of prostaglandins or oxygen radicals. He has proposed that inhibition of Na+, K+-ATPase activity by PGG2 may be a common mechanism leading to neuronal toxicity under conditions, such as the presence of ethanol, that promote increases in COX activity. Ongoing work is aimed at establishing the exact biochemical basis for the inhibition of Na+, K+-ATPase activity by PGG2. NOTE: Previously, the Principal Investigator of this project was Markku Linnoila, M.D., Ph.D., who died in February, 1998. The research conducted during this reporting period was performed by Dr. Timothy Foley.